The present invention relates to a system for monitoring the lyophilisation process of pharmaceutical products contained in vials and ampoules.
Lyophilisation is a well known drying process wherein the solvent, generally water, is removed by means of sublimation from the previously frozen product, by exploiting the combined action of low temperature and low pressure. It is useful to monitor the lyophilisation process in that this allows controlling the quality of the product and allows the development and implementation of specific optimisation and control strategies for the process itself. The temperature of the product is the most important variable to be monitored during the process. Indeed, the sublimation phase, known as primary drying, must be carried out at such a temperature as to avoid the formation of liquid, so that the fraction of the product already dried does not deteriorate thermally and break down.
Another important process variable is the position of the sublimation front within the product subjected to lyophilisation, which moves during the process, travelling from the top of the container to the bottom, until it disappears as soon as the frozen solvent has been completely removed. Hence, monitoring the position of the sublimation interface allows determining the state of progression of the primary drying phase and allows the establishment of when the sublimation process has terminated.
Two methods are used nowadays, at both the industrial and laboratory levels, for measuring the temperature of a product in a container associated with an external heating element (plate).
A first method consists of inserting a thermocouple inside the container. A thermocouple is inserted inside the container containing the product in the liquid state, generally placed in contact with the inner surface at the base of the container, or in another position. The value of the temperature measured is assumed to be representative of that of the entire product, even if a temperature gradient exists between the base of the container and the sublimation front, which is not known a priori. This measurement method is invasive, whereby the thermocouple disturbs both the exchanges of heat which are established between the various parts of the system and the physical freezing process. Indeed, even though the insertion of thin thermocouples into the vial is a widely used method for measuring the temperature of the product, it is well known that this procedure produces a change in the elementary nucleation phenomena and in the growth of ice crystals. The tip of the thermocouple acts as a heterogeneous nucleation site, and this leads to an increase in the mean ice crystal size, which leads to reduced matter transfer resistance during the primary drying phase. Furthermore, the presence of the probe body causes the formation of a preferential path for the water vapour molecules, causing a further reduction of mass transfer resistance in the dry layer. All the above effects lead to faster drying kinetics in relation to the monitored vials which, as a consequence, cannot be considered to be representative of the entire process. Furthermore, the insertion of the probe can compromise the sterility of pharmaceutical products.
A second method used involves measuring the temperature manometrically, and is known as “Manometric Temperature Measurement” (MTM). This method is based on measuring the increased pressure which occurs in the system when the valve separating the lyophilisation chamber from the condenser is closed for a few moments. The condenser, or ice trap, is a component of the lyophilisation device, the walls of which are maintained at a low temperature by means of the circulation of a refrigerant fluid. The temperature difference between the product and the temperature at the condenser represents the driving force behind the sublimation process. The vapour released from the product sublimes on the chilled condenser walls, thus maintaining the level of vacuum within the system. By means of certain mathematical models proposed in the literature, it is possible to relate the dynamics of the pressure increase to the sublimation temperature. This method is non-invasive, but does have several drawbacks: the lyophilisation device must be equipped with a condenser outside the lyophilisation chamber, the separation valve closure time must be extremely small, and measurement cannot be performed continuously, hence it provides discontinuous monitoring of the sublimation temperature; furthermore, it provides the mean value of all the vials and does not allow assessment of the non-uniformity between the vials or ampoules placed in different areas of the lyophilisation device. During measurement, the temperature of the product has a tendency to increase, especially in the final phase of primary drying, thus exposing the product to risk of break-down. It is also known that said method is not capable of providing accurate sublimation temperature values at the end of primary drying.
The following methods are currently available in relation to determining the state of progress of the primary drying phase:
1—insertion of thermocouples at various heights within the product container;
2—measuring of the mass of substance in the lyophilisation phase.
By means of the former method, when the sublimation front passes the temperature sensor, the temperature profile shows a sloping variation. In this way, by using various different thermocouples, it is possible to follow the temporal progression of the position of the moving interface. However, this method implies the use of a plurality of thermocouples inside the product, which have an influence on the mechanism of nucleation occurring during the freezing phase. For this reason, the measurements obtained this way cannot be considered as an absolute indication of the conditions prevailing in the non-monitored containers. Furthermore, for practical reasons, the simultaneous use of several thermocouples is limited to large sized containers only.
By means of the latter method it is indirectly deduced the position of the sublimation front inside the container knowing the initial mass of water in the solution, the dimensions of the container, and by measuring the mass of the substance. Of the various methods available for measuring mass, only those based on the use of special scales capable of operation under vacuum seem to disturb the process in a limited fashion, and hence, with appropriate contrivances, are the only methods capable of providing good results. Unfortunately, such scales are difficult to find, and are expensive.
An object of the present invention is that of allowing the realization of a system capable of determining the temperature profile and position of the sublimation front in real time during a lyophilisation process of substances contained in bottles, vials, small kegs, ampoules or similar containers.